Basics

Description

A potentially life-threatening drug-induced syndrome that results from synaptic increase in serotonin (5-hydroxytryptamine [5-HT]) concentrations and stimulation of peripheral and CNS serotonergic receptors

It is a concentration-dependent toxicity that can develop in any individual who has ingested drug combinations that synergistically increase synaptic 5-HT.

Serotonin toxicity occurs in three main settings: (i) therapeutic drug use, which often results in mild to moderate symptoms; (ii) intentional overdose of a single serotonergic agent, which typically leads to moderate symptoms; and (iii) as the result of a drug interaction between numerous serotonergic agents (most commonly, selective serotonin reuptake inhibitors [SSRIs] and monoamine oxidase inhibitors [MAOIs]), most often associated with severe serotonin toxicity.

Classically characterized by a triad of symptoms that include mental status change, neuromuscular hyperactivity, and autonomic instability

Onset is usually within 24 hours with 60% of cases occurring within 6 hours of exposure to, or change in, dosing of a serotonergic agent. Rarely, cases have been reported weeks after discontinuation of serotonergic agents.

Geriatric ConsiderationsIncreased risk through polypharmacy given frequent use of serotonergic analgesics, antibiotics, and antidepressants

Pediatric Considerations

Serotonin syndrome has similar manifestations in children and adults.

General management is unchanged in children, other than medication dosing.

Serotonin levels are increased from baseline during an uncomplicated pregnancy with preeclamptic patients demonstrating a 10-fold increase in serotonin levels.

3rd-trimester exposure to SSRIs has been associated with transient neonatal complications that may reflect either acute drug withdrawal or serotonergic toxicity.

Epidemiology

Seen in about 14–16% of SSRI overdose patients

Incidence

Approximately 100,000 adverse events, including deaths, are reported annually with antidepressant use. Most of which are associated with SSRIs, either alone or in combination with other drugs. In a 2008 study, SSRIs alone were responsible for adverse events in 18.8% of cases, with 55.7% due to intentional causes, 39.5% unintentional, and remainder of causes unknown. Of patients reporting adverse effects with SSRIs, 46.6% had symptoms requiring hospitalization, and significant toxic effects occurred in 90 patients with two resultant deaths (1)[A].

The incidence of serotonin syndrome is rising because serotonergic agents are increasingly used in clinical practice and in combination with other serotonergic agents. However, the true incidence is unclear due to potential misdiagnosis and unreported mild cases.

Risk Factors

Serotonergic agents

Comorbid conditions leading to polypharmacy

Reported following ingestion of a single agent

The greatest number of adverse events has been shown to be associated with SSRIs in combination with other substances, and the combination of SSRIs and MAOIs carries the greatest risk of developing serotonin toxicity.

General Prevention

Consider drug–drug interactions when a multidrug regimen is required and avoid if possible.

Basics

Description

A potentially life-threatening drug-induced syndrome that results from synaptic increase in serotonin (5-hydroxytryptamine [5-HT]) concentrations and stimulation of peripheral and CNS serotonergic receptors

It is a concentration-dependent toxicity that can develop in any individual who has ingested drug combinations that synergistically increase synaptic 5-HT.

Serotonin toxicity occurs in three main settings: (i) therapeutic drug use, which often results in mild to moderate symptoms; (ii) intentional overdose of a single serotonergic agent, which typically leads to moderate symptoms; and (iii) as the result of a drug interaction between numerous serotonergic agents (most commonly, selective serotonin reuptake inhibitors [SSRIs] and monoamine oxidase inhibitors [MAOIs]), most often associated with severe serotonin toxicity.

Classically characterized by a triad of symptoms that include mental status change, neuromuscular hyperactivity, and autonomic instability

Onset is usually within 24 hours with 60% of cases occurring within 6 hours of exposure to, or change in, dosing of a serotonergic agent. Rarely, cases have been reported weeks after discontinuation of serotonergic agents.

Geriatric ConsiderationsIncreased risk through polypharmacy given frequent use of serotonergic analgesics, antibiotics, and antidepressants

Pediatric Considerations

Serotonin syndrome has similar manifestations in children and adults.

General management is unchanged in children, other than medication dosing.

Serotonin levels are increased from baseline during an uncomplicated pregnancy with preeclamptic patients demonstrating a 10-fold increase in serotonin levels.

3rd-trimester exposure to SSRIs has been associated with transient neonatal complications that may reflect either acute drug withdrawal or serotonergic toxicity.

Epidemiology

Seen in about 14–16% of SSRI overdose patients

Incidence

Approximately 100,000 adverse events, including deaths, are reported annually with antidepressant use. Most of which are associated with SSRIs, either alone or in combination with other drugs. In a 2008 study, SSRIs alone were responsible for adverse events in 18.8% of cases, with 55.7% due to intentional causes, 39.5% unintentional, and remainder of causes unknown. Of patients reporting adverse effects with SSRIs, 46.6% had symptoms requiring hospitalization, and significant toxic effects occurred in 90 patients with two resultant deaths (1)[A].

The incidence of serotonin syndrome is rising because serotonergic agents are increasingly used in clinical practice and in combination with other serotonergic agents. However, the true incidence is unclear due to potential misdiagnosis and unreported mild cases.

Risk Factors

Serotonergic agents

Comorbid conditions leading to polypharmacy

Reported following ingestion of a single agent

The greatest number of adverse events has been shown to be associated with SSRIs in combination with other substances, and the combination of SSRIs and MAOIs carries the greatest risk of developing serotonin toxicity.

General Prevention

Consider drug–drug interactions when a multidrug regimen is required and avoid if possible.